- Email: [email protected]
ED presentation of neutropenic enterocolitis in adult patients with acute leukemia
ED Presentation of Neutropenic Enterocolitis in Adult Patients With Acute Leukemia TEH-FU HSU, MD,* HSIEN-HAO HUANG, MD,† DAVID HUNG-TSANG YEN, MD, PHD,†§ WEI-FONG KAO, MD,† JEN-DAR CHEN, MD,‡ LEE-MIN WANG, MD,† AND CHEN-HSEN LEE, MD† The purpose of this study was to investigate the initial clinical features and subsequent outcomes in patients with adult leukemia with typhlitis or neutropenic enterocolitis. A retrospective review of 10 episodes of neutropenic enterocolitis in nine patients (age range, 21-71 years) with acute leukemia from March 1, 1990, through February 28, 2002, was conducted. In clinical presentations, fever appears in all patients, followed by abdominal pain or tenderness (90%) and diarrhea (60%), respectively. In particular, three cases were coincidentally diagnosed as leukemia before any chemotherapy. The most common diagnostic modality used for the diagnosis of neutropenic enterocolitis was computed tomography (CT) scan (seven episodes). Medical treatments, including broad-spectrum antibiotics, bowel rest, and total parenteral nutrition, were applied to seven patients. Laparotomy with bowel resection was performed on two patients with bowel necrosis and severe peritonitis. Of all nine cases, six were fatal as a result of sepsis, a common complication of neutropenic enterocolitis. As the incidence of neutropenic enterocolitis increases in patients with acute leukemia, EPs should be alert and make an early diagnosis of this rapidly deteriorated and life-threatening disease. (Am J Emerg Med 2004;22:276-279. © 2004 Elsevier Inc. All rights reserved.)
Typhlitis, also known as neutropenic enterocolitis or ileocecal syndrome,1 is an inflammatory process involving segments of terminal ileum, ascending colon, and cecum that could progress to ulceration, necrosis, and perforation.2,3 This syndrome, clinically characterized by neutropenia, fever, and abdominal pain, seems to happen more frequently in patients with leukemia undergoing aggressively cytotoxic chemotherapy.4 Occasionally, neutropenic enterocolitis could also present in other immunocompromised patients, including malignant neoplasms,5 aplastic anemia,4 and acquired immunodeficiency syndrome6 in profound neutropenia state. In the review of the literature, only individual case reports7-9 of patients with acute leukemia with neutropenic enterocolitis before any chemotherapy had been demonstrated. Because of increasing incidence4,10 of this life-threatening disease entity,11 early diagnosis and an appropriately therapeutic program are the essential factors From the *Department of Emergency Medicine, Ton-Yen General Hospital; the †Departments of Emergency Medicine and ‡Radiology, Taipei-Veterans General Hospital, §Institute of Emergency and Critical Care Medicine, College of Medicine, National Yang-Ming University, Taiwan, R.O.C. Received April 15, 2003; accepted May 14, 2003. Address correspondence to David Hung-Tsang Yen, MD, PhD, Department of Emergency Medicine, Taipei-Veterans General Hospital 201 Sec 2, Shih-Pai Rd. Taipei, Taiwan, R.O.C. Email: [email protected] Key Words: Typhlitis, leukemia, emergency department © 2004 Elsevier Inc. All rights reserved. 0735-6757/04/2204-0008$30.00/0 doi:10.1016/j.ajem.2004.02.014 276
to improve survival rate. The purpose of this study was to demonstrate the clinical features and subsequent outcomes of neutropenic enterocolitis in nine adult patients with acute leukemia, among whom three patients with onset before diagnosis and chemotherapy of acute leukemia were encountered in the ED. METHODS Initial case findings were through a computer search of hospital discharges with the codes for typhlitis, enterocolitis, and its synonyms, including necrotizing colitis, neutropenic colitis, ileocecal syndrome, and cecitis. Patients younger than 14 years were excluded. Only patients with acute leukemia with a diagnosis of typhlitis confirmed by combination of clinical syndromes of fever, abdominal pain, and tenderness and evidence of surgical exploration, colonoscope, ultrasonography, or computed tomography (CT) were included in this study. Nine patients with 10 episodes met the inclusion criteria. We recorded the clinical features, including demographic data, initial signs and symptoms, predisposing disease, inducing factors, microorganisms from blood cultures, diagnostic tools, treatment programs, and prognosis. Survival indicated patients went through the episode and were discharged smoothly after this admission. Data were presented with mean ⫾ standard deviation. RESULTS From January 1990 through February 2002, 10 episodes in nine patients with neutropenic enterocolitis were identified. The ages of nine patients ranged from 21 to 63, with a mean age of 44.8 years. The white blood count ranged from 100 to 1,900 per L, with a mean of 770 (Table 1). The mean platelet counts was 64,000 per L. In initial clinical presentations, fever (100%) appears in every patient, followed by abdominal pain (90%) and diarrhea (60%). Table 2 demonstrated all patients had acute leukemia, either myeloid in eight or lymphatic in one. Of all nine patients, three cases of leukemia were found coincidentally and had not received any chemotherapy before diagnosis. A wide variety of microorganisms, including Aeromonas hydrophila, Clostridium difficile, Enterobacter cloacae and Klebsiella pneumoniae, were identified. The most common tool used for the diagnosis of neutropenic enterocolitis was CT scan in seven episodes. Medical treatment, including broad-spectrum antibiotics, total parenteral nutrition, and/or peripheral parenteral nutrition, was applied on seven patients. Laparotomy was performed in two patients with bowel necrosis
HSU ET AL ■ NEUTROPENIC ENTEROCOLITIS IN LEUKEMIA PATIENTS
TABLE 1. Summary of Demographic Data and Clinical Characteristics in Nine Patients (10 episodes) With Neutropenic Enterocolitis Characteristics
N ⫽ 10
Age (y)* Male: female White blood count (per L)* Hospital days* Initial clinical signs and symptoms Fever Generalized abdominal pain or tenderness Loosely or watery diarrhea Tenderness localized in the right lower quadrant of the abdomen Tarry or bloody stool Nausea or vomiting Abdominal distension Rebounding pain Hematemesis Jaundice
44.8 ⫾ 16.2 1:1 770 ⫾ 596 20.2 ⫾ 11.3 N (%) 10 (100) 9 (90) 6 (60) 4 (40) 4 4 4 3 2 1
(40) (40) (40) (30) (20) (10)
*Mean ⫾ standard deviation
and peritonitis. Of all nine patients, six died of severe sepsis, which is a common complication of neutropenic enterocolitis. DISCUSSION Neutropenic enterocolitis, an unusual presentation of abdominal infection mostly in patients with leukemia after chemotherapy, was an ominous complication with high mortality rate ranging from 50% to 100%.11-13 Early diagTABLE 2.
277
nosis and collaborative medical and surgical management of this disease are mandatory for the improvement of survival rate. The classic clinical features of neutropenic enterocolitis in patients with leukemia or lymphoma are fever, diarrhea, and lower quadrant pain of the abdomen during the neutropenic state caused by cytotoxic chemotherapy.2,4 Generalized abdominal pain was reported in three-fourths of patients with neutropenic enterocolitis, whereas 60% to 69% of patients had localized tenderness in the right lower quadrant of abdomen.11,14 This case-series study demonstrated, in addition to neutropenia, the most common clinical presentations were fever, followed by generalized abdominal pain or tenderness and diarrhea, indicating a protracted course of intestinal inflammation. A particular finding in this study is that three patients presented in the ED before any chemotherapy with clinical characteristics suggesting the diagnosis of neutropenic enterocolitis and compatible with typical imaging of CT scan. EPs must have a high index of suspicion of this uncommon disease, identify this process, and take prompt diagnostic and treatment strategies to improve outcomes. The diagnostic features of neutropenic enterocolitis have been described by plain radiographs,4 barium enema,15 ultrasonography.16,17 Sonography can be used as a tool to initially detect suspected patients with typhlitis,18 follow the clinical course of the patients,17 and prevent underestimated abdominal infection victims.10 CT can demonstrate diffuse submucosal thickening and swelling of the terminal ileum and ascending colon (Fig 1), accumulation of paracolonic fluid, inflammatory bowel changes, and gas formation in both bowel wall and peritoneum in this and other stud-
Individual Clinical Presentations, Treatments, and Prognosis in Nine Patients (10 episodes) with Neutropenic Enterocolitis
Patient No.
Age (yrs)/ Sex
Predisposing Disease
WBC counts (L)
Platelet (L)
Blood Culture
1-1
38/F
AML
I
200
37,000
1-2 2 3
38/F 54/F 43/F
AML AML AML
M M M
1,400 800 600
45,000 16,000 34,000
4
42/M
AML
M
100
32,000
5 6 7
55/F 21/M 63/M
AML AML AML
I I N/A
300 300 1,900
3,000 12,000 402,000
8 9
71/M 23/M
ALL AML
N/A N/A
800 1,300
7,000 56,000
Inducing Factor
Diagnostic Tools
Treatments*
Prognosis
Aeromonas hydrophila Nil Nil Enterobacter cloacae Nil
Colonscope,
Medical
Survival
US CT, US US
Medical Medical Medical
Survival Mortality Survival
CT, Expl
Mortality
Nil Nil Clostridium difficle, Klebsiella pneumoniae Nil Nil
CT, US CT, Colonscope CT
Medical and surgical Medical Medical Medical
Medical Medical and surgical
Mortality Mortality
CT CT, Expl
Mortality Survival Mortality†
Abbreviations: WBC, white blood cell; AML, acute myeloblastic leukemia; I, induction chemotherapy; M, maintaining chemotherapy; CT, computed tomography; US, ultrasonography; Expl, exploratory laparotomy; N/A, not accessible; ALL, acute lymphocytic leukemia. *Medical treatment included broad-spectrum antibiotics, total parenteral nutrition, and/or peripheral parenteral nutrition. Surgical treatment indicated exploratory laparotomy. †This patient was dead as a result of severe sepsis after induction chemotherapy.
278
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 4 ■ July 2004
FIGURE 1. Contrast-enhanced computed tomography of the abdomen demonstrated marked bowel wall thickening with submucosal edema of ascending colon (A, white arrow), cecum (B, white arrowhead), and terminal ileum (B, white arrow). Mesenteric infiltrates (black arrow) and fluid were also noted over the right lower abdomen just around the ascending colon and ileocecal region.
HSU ET AL ■ NEUTROPENIC ENTEROCOLITIS IN LEUKEMIA PATIENTS
ies.19,20 The CT scans can provide a more accurate differential diagnoses and indicate surgical or medical treatment, decreasing the negative exploration rate.21,22 CT is thus recommended to provide more informative evaluation and therapeutic guidance23 for the determination of risk stratification of patients with diffuse or lower abdominal pain. The pathogenesis of neutropenic enterocolitis remains unclear, but felt to involve initially cecal mucosal damage, followed by inflammation and edema, then progress to ulceration, transmural necrosis, and perforation.11,14 Damaged integrity of the colonic mucosa, altered bacterial flora, and decreased host defense and blood flow of the colon could contribute to typhlitis.24-26 In this study, we found neutropenic enterocolitis in three patients with acute leukemia before any induction or maintenance of chemotherapeutic agents. This finding suggests although chemotherapy could be one of the predisposing factors, it is not an essential in the genesis of neutropenic enterocolitis. The management of neutropenic enterocolitis remains controversial. Timely conservative treatment, including antibiotics, bowel rest, institution of fluid or blood products, and correction of electrolyte imbalance, frequently allow resolution of neutropenic enterocolitis without operation.4,23 Several reports11,26,27 advocate selective surgical management was indicated for these patients with severe presentations and complications such as abscess, gangrenous bowel, perforation, massive gastrointestinal tract bleeding, and obstruction. EPs must be vigilant to identify this diagnosis and initiate aggressive medical treatment, and to consult a surgeon and oncologist for advanced managements of patients with neutropenic enterocolitis in the ED.20 Poor prognostic factors for these patients include shock, persistent septic syndrome, and prolonged neutropenia20,28 in clinical presentations. Cartoni et al.18 demonstrated patients with neutropenic enterocolitis with bowel wall thickness ⬎10 mm detected by ultrasonography had a significantly higher mortality rate (60%) than did those with bowel wall thickness ⱕ10 mm (4.2%, P ⬍.001). This result provides an immediately objective real-time evaluation of severity in clinical application in the ED. This case series study did not enroll some patients with mild neutropenic enterocolitis without significant image findings under our selection criteria. This would not represent variable spectrums in clinical presentations of this disease entity. We also excluded patients with solid tumor, immunodeficiency, and other malignancy in the development of neutropenic enterocolitis. In conclusion, with specific clinical presentations and a high mortality rate, neutropenic enterocolitis in adult patients with acute leukemia occurred mostly after (and occasionally before) the course of chemotherapy. It is incumbent on EPs to promptly initiate diagnostic radiography and aggressive supportive management with early surgical consultation to increase the survival rate of this often deadly disease. REFERENCES 1. Sherman N, Woolley M: The ileocecal syndrome in acute childhood leukemia. Arch Surg 1973;107:39-42
279
2. Steinberg D, Gold J, Brodin A: Necrotizing enterocolitis in leukemia. Arch Intern Med 1973;131:538-544 3. Weinberger M, Hollingsworth H, Feurestein IM, et al: Successful surgical management of neutropenic enterocolitis in two patients with severe aplastic anemia. Arch Intern Med 1993;153:107-113 4. Sloas MM, Flynn PM, Kaste SC, et al: Typhlitis in children with cancer: a 30-year experience. Clin Infect Dis 1993;17:484-490 5. Pestalozzi BC, Sotos GA, Choyke PL, et al: Typhlitis resulting from treatment with Taxol and doxorubicin in patients with metastatic breast cancer. Cancer 1993;71:1797-1800 6. Cutrona AF, Blinkhom RJ, Crass J, et al: Probable neutropenic enterocolitis in patients with AIDS. Rev Infect Dis 1991;13:828-831 7. Ahsan N, Sun CJ, Di John D: Acute ileotyphlitis as presenting manifestation of acute myelogenous leukemia. Am J Clin Pathol 1988;89:407-409 8. Paulino AFG, Kenney R, Forman EN, et al: Typhlitis in a patient with acute lymphoblastic leukemia prior to the administration of chemotherapy. Am J Pediatr Hematol Oncol 1994;16:348-351 9. D’Souza S, Lindberg M: Typhlitis as a presenting manifestation of acute myelogenous leukemia. South Med J 2000;93:218-220 10. Gorschluter M, Marklein G, Hofling K, et al: Abdominal infections in patients with acute leukaemia: a prospective study applying ultrasonography and microbiology. Br J Haematol 2002;117:351358 11. Wade DS, Nava HR, Douglass HO Jr: Neutropenic enterocolitis. Clinical diagnosis and treatment. Cancer 1992;69:17-23 12. Nagler A, Pavel L, Naparstek E, et al: Typhlitis occurring in autologous bone marrow transplantation. Bone Marrow Transplant 1992;9:63-64 13. Shamberger RC, Weinstein HJ, Delorey MJ, et al: The medical and surgical management of typhlitis in children with acute nonlymphocytic (myelogenous) leukemia. Cancer 1986;57:603-609 14. Dosik GM, Luna M, Valdivieso M, et al: Necrotizing colitis in patients with cancer. Am J Med 1979;67:646-656 15. Taylor AJ, Dodds WJ, Gonyo JE, et al: Typhlitis in adults. Gastrointest Radiol 1985;10:363-369 16. Alexander JE, Williamson SL, Seibert JJ, et al: The ultrasonographic diagnosis of typhlitis (neutropenic colitis). Pediatr Radiol 1988;18:200-204 17. Teefey SA, Montana MA, Goldfogel GA, et al: Sonographic diagnosis of neutropenic typhlitis. AJR Am J Roentgenol 1987;149: 731-733 18. Cartoni C, Dragoni F, Micozzi A, et al: Neutropenic enterocolitis in patients with acute leukemia: prognostic significance of bowel wall thickening detected by ultrasonography. J Clin Oncol 2001;19:756-761 19. Adams GW, Rauch RF, Kelvin FM, et al: CT detection of typhlitis. J Comput Assist Tomogr 1985;9:363-365 20. de Brito D, Barton E, Spears KL, et al: Acute right lower quadrant pain in a patient with leukemia. Ann Emerg Med 1998;32: 98-101 21. Liu CC, Lu CL, Yen DHT, et al: Diagnosis of appendicitis in the ED: comparison of surgical and nonsurgical residents. Am J Emerg Med 2001;19:109-112 22. Horton MD, Counter SF, Florence MG, et al: A prospective trial of computed tomography and ultrasonography for diagnosing appendicitis in the atypical patient. Am J Surg 2000;179:379-381 23. Song HK, Kreisel D, Canter R, et al: Changing presentation and management of neutropenic enterocolitis. Arch Surg 1998;133: 979-982 24. Musher DR, Amorosi EL, Gouge T, et al: Neutropenic typhlitis simulating carcinoma of the cecum. Gastrointest Endosc 1989;35: 449-451 25. Dworkin B, Winawer SJ, Lightdale CJ: Typhlitis: report of a case with long-term survival and a review of the recent literature. Dig Dis Sci 1981;26:1032-1037 26. Keidan RD, Fanning J, Gatenby RA, et al: Recurrent typhlitis: a disease resulting from aggressive chemotherapy. Dis Colon Rectum 1989;32:206-209 27. Moir CR, Scudamore CH, Benny WB: Typhlitis: selective surgical management. Am J Surg 1986;151:563-566 28. Buyukasik Y, Ozcebe OI, Haznedaroglu IC, et al: Neutropenic enterocolitis in adult leukemias. Int J Hematol 1997;66:47-55
Typhlitis, also known as neutropenic enterocolitis or ileocecal syndrome,1 is an inflammatory process involving segments of terminal ileum, ascending colon, and cecum that could progress to ulceration, necrosis, and perforation.2,3 This syndrome, clinically characterized by neutropenia, fever, and abdominal pain, seems to happen more frequently in patients with leukemia undergoing aggressively cytotoxic chemotherapy.4 Occasionally, neutropenic enterocolitis could also present in other immunocompromised patients, including malignant neoplasms,5 aplastic anemia,4 and acquired immunodeficiency syndrome6 in profound neutropenia state. In the review of the literature, only individual case reports7-9 of patients with acute leukemia with neutropenic enterocolitis before any chemotherapy had been demonstrated. Because of increasing incidence4,10 of this life-threatening disease entity,11 early diagnosis and an appropriately therapeutic program are the essential factors From the *Department of Emergency Medicine, Ton-Yen General Hospital; the †Departments of Emergency Medicine and ‡Radiology, Taipei-Veterans General Hospital, §Institute of Emergency and Critical Care Medicine, College of Medicine, National Yang-Ming University, Taiwan, R.O.C. Received April 15, 2003; accepted May 14, 2003. Address correspondence to David Hung-Tsang Yen, MD, PhD, Department of Emergency Medicine, Taipei-Veterans General Hospital 201 Sec 2, Shih-Pai Rd. Taipei, Taiwan, R.O.C. Email: [email protected] Key Words: Typhlitis, leukemia, emergency department © 2004 Elsevier Inc. All rights reserved. 0735-6757/04/2204-0008$30.00/0 doi:10.1016/j.ajem.2004.02.014 276
to improve survival rate. The purpose of this study was to demonstrate the clinical features and subsequent outcomes of neutropenic enterocolitis in nine adult patients with acute leukemia, among whom three patients with onset before diagnosis and chemotherapy of acute leukemia were encountered in the ED. METHODS Initial case findings were through a computer search of hospital discharges with the codes for typhlitis, enterocolitis, and its synonyms, including necrotizing colitis, neutropenic colitis, ileocecal syndrome, and cecitis. Patients younger than 14 years were excluded. Only patients with acute leukemia with a diagnosis of typhlitis confirmed by combination of clinical syndromes of fever, abdominal pain, and tenderness and evidence of surgical exploration, colonoscope, ultrasonography, or computed tomography (CT) were included in this study. Nine patients with 10 episodes met the inclusion criteria. We recorded the clinical features, including demographic data, initial signs and symptoms, predisposing disease, inducing factors, microorganisms from blood cultures, diagnostic tools, treatment programs, and prognosis. Survival indicated patients went through the episode and were discharged smoothly after this admission. Data were presented with mean ⫾ standard deviation. RESULTS From January 1990 through February 2002, 10 episodes in nine patients with neutropenic enterocolitis were identified. The ages of nine patients ranged from 21 to 63, with a mean age of 44.8 years. The white blood count ranged from 100 to 1,900 per L, with a mean of 770 (Table 1). The mean platelet counts was 64,000 per L. In initial clinical presentations, fever (100%) appears in every patient, followed by abdominal pain (90%) and diarrhea (60%). Table 2 demonstrated all patients had acute leukemia, either myeloid in eight or lymphatic in one. Of all nine patients, three cases of leukemia were found coincidentally and had not received any chemotherapy before diagnosis. A wide variety of microorganisms, including Aeromonas hydrophila, Clostridium difficile, Enterobacter cloacae and Klebsiella pneumoniae, were identified. The most common tool used for the diagnosis of neutropenic enterocolitis was CT scan in seven episodes. Medical treatment, including broad-spectrum antibiotics, total parenteral nutrition, and/or peripheral parenteral nutrition, was applied on seven patients. Laparotomy was performed in two patients with bowel necrosis
HSU ET AL ■ NEUTROPENIC ENTEROCOLITIS IN LEUKEMIA PATIENTS
TABLE 1. Summary of Demographic Data and Clinical Characteristics in Nine Patients (10 episodes) With Neutropenic Enterocolitis Characteristics
N ⫽ 10
Age (y)* Male: female White blood count (per L)* Hospital days* Initial clinical signs and symptoms Fever Generalized abdominal pain or tenderness Loosely or watery diarrhea Tenderness localized in the right lower quadrant of the abdomen Tarry or bloody stool Nausea or vomiting Abdominal distension Rebounding pain Hematemesis Jaundice
44.8 ⫾ 16.2 1:1 770 ⫾ 596 20.2 ⫾ 11.3 N (%) 10 (100) 9 (90) 6 (60) 4 (40) 4 4 4 3 2 1
(40) (40) (40) (30) (20) (10)
*Mean ⫾ standard deviation
and peritonitis. Of all nine patients, six died of severe sepsis, which is a common complication of neutropenic enterocolitis. DISCUSSION Neutropenic enterocolitis, an unusual presentation of abdominal infection mostly in patients with leukemia after chemotherapy, was an ominous complication with high mortality rate ranging from 50% to 100%.11-13 Early diagTABLE 2.
277
nosis and collaborative medical and surgical management of this disease are mandatory for the improvement of survival rate. The classic clinical features of neutropenic enterocolitis in patients with leukemia or lymphoma are fever, diarrhea, and lower quadrant pain of the abdomen during the neutropenic state caused by cytotoxic chemotherapy.2,4 Generalized abdominal pain was reported in three-fourths of patients with neutropenic enterocolitis, whereas 60% to 69% of patients had localized tenderness in the right lower quadrant of abdomen.11,14 This case-series study demonstrated, in addition to neutropenia, the most common clinical presentations were fever, followed by generalized abdominal pain or tenderness and diarrhea, indicating a protracted course of intestinal inflammation. A particular finding in this study is that three patients presented in the ED before any chemotherapy with clinical characteristics suggesting the diagnosis of neutropenic enterocolitis and compatible with typical imaging of CT scan. EPs must have a high index of suspicion of this uncommon disease, identify this process, and take prompt diagnostic and treatment strategies to improve outcomes. The diagnostic features of neutropenic enterocolitis have been described by plain radiographs,4 barium enema,15 ultrasonography.16,17 Sonography can be used as a tool to initially detect suspected patients with typhlitis,18 follow the clinical course of the patients,17 and prevent underestimated abdominal infection victims.10 CT can demonstrate diffuse submucosal thickening and swelling of the terminal ileum and ascending colon (Fig 1), accumulation of paracolonic fluid, inflammatory bowel changes, and gas formation in both bowel wall and peritoneum in this and other stud-
Individual Clinical Presentations, Treatments, and Prognosis in Nine Patients (10 episodes) with Neutropenic Enterocolitis
Patient No.
Age (yrs)/ Sex
Predisposing Disease
WBC counts (L)
Platelet (L)
Blood Culture
1-1
38/F
AML
I
200
37,000
1-2 2 3
38/F 54/F 43/F
AML AML AML
M M M
1,400 800 600
45,000 16,000 34,000
4
42/M
AML
M
100
32,000
5 6 7
55/F 21/M 63/M
AML AML AML
I I N/A
300 300 1,900
3,000 12,000 402,000
8 9
71/M 23/M
ALL AML
N/A N/A
800 1,300
7,000 56,000
Inducing Factor
Diagnostic Tools
Treatments*
Prognosis
Aeromonas hydrophila Nil Nil Enterobacter cloacae Nil
Colonscope,
Medical
Survival
US CT, US US
Medical Medical Medical
Survival Mortality Survival
CT, Expl
Mortality
Nil Nil Clostridium difficle, Klebsiella pneumoniae Nil Nil
CT, US CT, Colonscope CT
Medical and surgical Medical Medical Medical
Medical Medical and surgical
Mortality Mortality
CT CT, Expl
Mortality Survival Mortality†
Abbreviations: WBC, white blood cell; AML, acute myeloblastic leukemia; I, induction chemotherapy; M, maintaining chemotherapy; CT, computed tomography; US, ultrasonography; Expl, exploratory laparotomy; N/A, not accessible; ALL, acute lymphocytic leukemia. *Medical treatment included broad-spectrum antibiotics, total parenteral nutrition, and/or peripheral parenteral nutrition. Surgical treatment indicated exploratory laparotomy. †This patient was dead as a result of severe sepsis after induction chemotherapy.
278
AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 4 ■ July 2004
FIGURE 1. Contrast-enhanced computed tomography of the abdomen demonstrated marked bowel wall thickening with submucosal edema of ascending colon (A, white arrow), cecum (B, white arrowhead), and terminal ileum (B, white arrow). Mesenteric infiltrates (black arrow) and fluid were also noted over the right lower abdomen just around the ascending colon and ileocecal region.
HSU ET AL ■ NEUTROPENIC ENTEROCOLITIS IN LEUKEMIA PATIENTS
ies.19,20 The CT scans can provide a more accurate differential diagnoses and indicate surgical or medical treatment, decreasing the negative exploration rate.21,22 CT is thus recommended to provide more informative evaluation and therapeutic guidance23 for the determination of risk stratification of patients with diffuse or lower abdominal pain. The pathogenesis of neutropenic enterocolitis remains unclear, but felt to involve initially cecal mucosal damage, followed by inflammation and edema, then progress to ulceration, transmural necrosis, and perforation.11,14 Damaged integrity of the colonic mucosa, altered bacterial flora, and decreased host defense and blood flow of the colon could contribute to typhlitis.24-26 In this study, we found neutropenic enterocolitis in three patients with acute leukemia before any induction or maintenance of chemotherapeutic agents. This finding suggests although chemotherapy could be one of the predisposing factors, it is not an essential in the genesis of neutropenic enterocolitis. The management of neutropenic enterocolitis remains controversial. Timely conservative treatment, including antibiotics, bowel rest, institution of fluid or blood products, and correction of electrolyte imbalance, frequently allow resolution of neutropenic enterocolitis without operation.4,23 Several reports11,26,27 advocate selective surgical management was indicated for these patients with severe presentations and complications such as abscess, gangrenous bowel, perforation, massive gastrointestinal tract bleeding, and obstruction. EPs must be vigilant to identify this diagnosis and initiate aggressive medical treatment, and to consult a surgeon and oncologist for advanced managements of patients with neutropenic enterocolitis in the ED.20 Poor prognostic factors for these patients include shock, persistent septic syndrome, and prolonged neutropenia20,28 in clinical presentations. Cartoni et al.18 demonstrated patients with neutropenic enterocolitis with bowel wall thickness ⬎10 mm detected by ultrasonography had a significantly higher mortality rate (60%) than did those with bowel wall thickness ⱕ10 mm (4.2%, P ⬍.001). This result provides an immediately objective real-time evaluation of severity in clinical application in the ED. This case series study did not enroll some patients with mild neutropenic enterocolitis without significant image findings under our selection criteria. This would not represent variable spectrums in clinical presentations of this disease entity. We also excluded patients with solid tumor, immunodeficiency, and other malignancy in the development of neutropenic enterocolitis. In conclusion, with specific clinical presentations and a high mortality rate, neutropenic enterocolitis in adult patients with acute leukemia occurred mostly after (and occasionally before) the course of chemotherapy. It is incumbent on EPs to promptly initiate diagnostic radiography and aggressive supportive management with early surgical consultation to increase the survival rate of this often deadly disease. REFERENCES 1. Sherman N, Woolley M: The ileocecal syndrome in acute childhood leukemia. Arch Surg 1973;107:39-42
279
2. Steinberg D, Gold J, Brodin A: Necrotizing enterocolitis in leukemia. Arch Intern Med 1973;131:538-544 3. Weinberger M, Hollingsworth H, Feurestein IM, et al: Successful surgical management of neutropenic enterocolitis in two patients with severe aplastic anemia. Arch Intern Med 1993;153:107-113 4. Sloas MM, Flynn PM, Kaste SC, et al: Typhlitis in children with cancer: a 30-year experience. Clin Infect Dis 1993;17:484-490 5. Pestalozzi BC, Sotos GA, Choyke PL, et al: Typhlitis resulting from treatment with Taxol and doxorubicin in patients with metastatic breast cancer. Cancer 1993;71:1797-1800 6. Cutrona AF, Blinkhom RJ, Crass J, et al: Probable neutropenic enterocolitis in patients with AIDS. Rev Infect Dis 1991;13:828-831 7. Ahsan N, Sun CJ, Di John D: Acute ileotyphlitis as presenting manifestation of acute myelogenous leukemia. Am J Clin Pathol 1988;89:407-409 8. Paulino AFG, Kenney R, Forman EN, et al: Typhlitis in a patient with acute lymphoblastic leukemia prior to the administration of chemotherapy. Am J Pediatr Hematol Oncol 1994;16:348-351 9. D’Souza S, Lindberg M: Typhlitis as a presenting manifestation of acute myelogenous leukemia. South Med J 2000;93:218-220 10. Gorschluter M, Marklein G, Hofling K, et al: Abdominal infections in patients with acute leukaemia: a prospective study applying ultrasonography and microbiology. Br J Haematol 2002;117:351358 11. Wade DS, Nava HR, Douglass HO Jr: Neutropenic enterocolitis. Clinical diagnosis and treatment. Cancer 1992;69:17-23 12. Nagler A, Pavel L, Naparstek E, et al: Typhlitis occurring in autologous bone marrow transplantation. Bone Marrow Transplant 1992;9:63-64 13. Shamberger RC, Weinstein HJ, Delorey MJ, et al: The medical and surgical management of typhlitis in children with acute nonlymphocytic (myelogenous) leukemia. Cancer 1986;57:603-609 14. Dosik GM, Luna M, Valdivieso M, et al: Necrotizing colitis in patients with cancer. Am J Med 1979;67:646-656 15. Taylor AJ, Dodds WJ, Gonyo JE, et al: Typhlitis in adults. Gastrointest Radiol 1985;10:363-369 16. Alexander JE, Williamson SL, Seibert JJ, et al: The ultrasonographic diagnosis of typhlitis (neutropenic colitis). Pediatr Radiol 1988;18:200-204 17. Teefey SA, Montana MA, Goldfogel GA, et al: Sonographic diagnosis of neutropenic typhlitis. AJR Am J Roentgenol 1987;149: 731-733 18. Cartoni C, Dragoni F, Micozzi A, et al: Neutropenic enterocolitis in patients with acute leukemia: prognostic significance of bowel wall thickening detected by ultrasonography. J Clin Oncol 2001;19:756-761 19. Adams GW, Rauch RF, Kelvin FM, et al: CT detection of typhlitis. J Comput Assist Tomogr 1985;9:363-365 20. de Brito D, Barton E, Spears KL, et al: Acute right lower quadrant pain in a patient with leukemia. Ann Emerg Med 1998;32: 98-101 21. Liu CC, Lu CL, Yen DHT, et al: Diagnosis of appendicitis in the ED: comparison of surgical and nonsurgical residents. Am J Emerg Med 2001;19:109-112 22. Horton MD, Counter SF, Florence MG, et al: A prospective trial of computed tomography and ultrasonography for diagnosing appendicitis in the atypical patient. Am J Surg 2000;179:379-381 23. Song HK, Kreisel D, Canter R, et al: Changing presentation and management of neutropenic enterocolitis. Arch Surg 1998;133: 979-982 24. Musher DR, Amorosi EL, Gouge T, et al: Neutropenic typhlitis simulating carcinoma of the cecum. Gastrointest Endosc 1989;35: 449-451 25. Dworkin B, Winawer SJ, Lightdale CJ: Typhlitis: report of a case with long-term survival and a review of the recent literature. Dig Dis Sci 1981;26:1032-1037 26. Keidan RD, Fanning J, Gatenby RA, et al: Recurrent typhlitis: a disease resulting from aggressive chemotherapy. Dis Colon Rectum 1989;32:206-209 27. Moir CR, Scudamore CH, Benny WB: Typhlitis: selective surgical management. Am J Surg 1986;151:563-566 28. Buyukasik Y, Ozcebe OI, Haznedaroglu IC, et al: Neutropenic enterocolitis in adult leukemias. Int J Hematol 1997;66:47-55